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International Journal of Molecular... May 2023Megakaryocytes are the main members of the hematopoietic system responsible for regulating vascular homeostasis through their progeny platelets, which are generally... (Review)
Review
Megakaryocytes are the main members of the hematopoietic system responsible for regulating vascular homeostasis through their progeny platelets, which are generally known for maintaining hemostasis. Megakaryocytes are characterized as large polyploid cells that reside in the bone marrow but may also circulate in the vasculature. They are generated directly or through a multi-lineage commitment step from the most primitive progenitor or Hematopoietic Stem Cells (HSCs) in a process called "megakaryopoiesis". Immature megakaryocytes enter a complicated development process defined as "thrombopoiesis" that ultimately results in the release of extended protrusions called proplatelets into bone marrow sinusoidal or lung microvessels. One of the main mediators that play an important modulatory role in hematopoiesis and hemostasis is nitric oxide (NO), a free radical gas produced by three isoforms of nitric oxide synthase within the mammalian cells. In this review, we summarize the effect of NO and its signaling on megakaryopoiesis and thrombopoiesis under both physiological and pathophysiological conditions.
Topics: Animals; Megakaryocytes; Nitric Oxide; Blood Platelets; Thrombopoiesis; Hematopoietic Stem Cells; Mammals
PubMed: 37175857
DOI: 10.3390/ijms24098145 -
Cytokine Nov 2021The blood vascular system of mammals is unique in nature; inhabited with a pool of tiny small cell fragments called platelets; attributed with the most important... (Review)
Review
The blood vascular system of mammals is unique in nature; inhabited with a pool of tiny small cell fragments called platelets; attributed with the most important patrolling tasks to check integrity of the entire endothelial landscape. Their production is tightly coupled with hematopoietic system where everything starts from self renewable multipotent hematopoietic stem cells (HSCs) which eventually undergo dual step (megakaryopoiesis-thrombopoiesis) thrombocytes production. Several cytokines tune the fate of every progenitor cells during hematopoiesis through temporal activation of specific transcription factors. Though platelets generated through steady state hematopoiesis are involved in the regulation of vascular homeostasis, these cells can sense pathogens through its innate immune sensors and can mount crucial responses against the invading pathogen. For this, the primary aim of many infections including Leishmania is to induce thrombocytopenia within infected host. But the underlying mechanism of this induced thrombocytopenia in Leishmania infection has not been evaluated. Elucidation of these mechanisms will be fruitful to design new chemotherapeutic strategies.
Topics: Animals; Cytokines; Hematopoietic Stem Cells; Humans; Immunity, Innate; Leishmaniasis; Thrombocytopenia; Thrombopoiesis
PubMed: 33127256
DOI: 10.1016/j.cyto.2020.155310 -
Journal of Cell Science Oct 2020The main function of blood platelets is to ensure hemostasis and prevent hemorrhages. The 10 platelets needed daily are produced in a well-orchestrated process. However,... (Review)
Review
The main function of blood platelets is to ensure hemostasis and prevent hemorrhages. The 10 platelets needed daily are produced in a well-orchestrated process. However, this process is not yet fully understood and platelet production is still inefficient. Platelets are produced in the bone marrow by megakaryocytes, highly specialized precursor cells that extend cytoplasmic projections called proplatelets (PPTs) through the endothelial barrier of sinusoid vessels. In this Cell Science at a Glance article and the accompanying poster we discuss the mechanisms and pathways involved in megakaryopoiesis and platelet formation processes. We especially address the - still underestimated - role of the microenvironment of the bone marrow, and present recent findings on how PPT extension differs from that and entails different mechanisms. Finally, we recapitulate old but recently revisited evidence that - although bone marrow does produce megakaryocytes and PPTs - remodeling and the release of bona fide platelets, mainly occur in the downstream microcirculation.
Topics: Blood Platelets; Bone Marrow; Cytoplasm; Megakaryocytes; Thrombopoiesis
PubMed: 33127839
DOI: 10.1242/jcs.244731 -
Radiation Research Dec 2011Hematopoietic processes, especially megakaryocytopoiesis and thrombopoiesis, are highly sensitive to extracellular oxidative stresses such as ionizing radiation and...
Hematopoietic processes, especially megakaryocytopoiesis and thrombopoiesis, are highly sensitive to extracellular oxidative stresses such as ionizing radiation and chemotherapeutic agents. This study examined the terminal maturation of megakaryocytes and platelet production in hematopoietic stem/progenitor cells (HSPCs) exposed to ionizing radiation. Highly purified CD34(+) cells derived from human placental/umbilical cord blood were exposed to X rays (2 Gy, 150 kVp, 20 mA; 0.5-mm aluminum and 0.3-mm copper filters) at a dose rate of approximately 1 Gy/min and then cultured in a serum-free medium supplemented with thrombopoietin and interleukin-3. The number of cells generated from X-irradiated CD34(+) cells decreased with the time in culture. However, the fraction of CD34(+)Tie-2(+) and CD41(+)Tie-2(+) cells among the total cells generated from X-irradiated cells increased significantly in comparison to nonirradiated controls on day 7. In addition, the CD42a(+) particles, which appeared to be platelets, generated from the X-irradiated HSPCs appeared to be normal. Quantitative real-time reverse transcriptase-polymerase chain reaction analysis of the expression of various genes in cells harvested from the cultures showed that the early hematopoiesis-related genes FLI1, HOXB4 and Tie-2, the cytokine receptor genes KIT and IL3RA, and the oxidative stress-related genes HO1 and NQO1 were upregulated on day 7. These results suggest that normal terminal maturation of megakaryocytes and platelet production occur in residual HSPCs after exposure to ionizing radiation despite the adverse effect of radiation on proliferation and differentiation of HSPCs. Ionizing radiation may have the potential to promote both megakaryocytopoiesis and thrombopoiesis.
Topics: Antigens, CD34; Blood Platelets; Female; Fetal Blood; Gene Expression Regulation; Hematopoietic Stem Cells; Humans; Interleukin-3; Megakaryocytes; Placenta; Platelet Membrane Glycoprotein IIb; Pregnancy; RNA, Messenger; Radiation Dosage; Thrombopoiesis; Thrombopoietin
PubMed: 22026586
DOI: 10.1667/rr2725.1 -
Blood Aug 2007PECAM-1 (CD31) knockout (KO) mice exhibit excessive megakaryocytopoiesis accompanied by increased numbers of megakaryocytes associated with the stromal niche rather than...
PECAM-1 (CD31) knockout (KO) mice exhibit excessive megakaryocytopoiesis accompanied by increased numbers of megakaryocytes associated with the stromal niche rather than the vascular niche. During earlier stages of megakaryocytopoiesis in KO marrow, an expanded Lin(-)Sca-1(+) c-kit(+) hematopoietic stem cell (HSC) population and increased quiescent Lin(-) progenitor pool were identified. During the later stages of megakaryocytopoiesis, CD31KO megakaryocytes exhibited abnormal adhesion/transmigration behaviors. Lastly, KO animals exhibited excessive splenic extramedullary megakaryocytopoiesis, which likely compensates for the impaired marrow megakaryocytopoiesis, resulting in normal peripheral platelet number. Thus, PECAM-1 modulates megakaryocytopoiesis in a hierarchic manner, functioning as a thermostat to "fine-tune" megakaryocytopoiesis.
Topics: Animals; Antigens, Ly; Blood Platelets; Bone Marrow; Cell Movement; Hematopoiesis, Extramedullary; Hematopoietic Stem Cells; Megakaryocytes; Membrane Proteins; Mice; Mice, Knockout; Platelet Count; Platelet Endothelial Cell Adhesion Molecule-1; Proto-Oncogene Proteins c-kit; Spleen; Thrombopoiesis
PubMed: 17412889
DOI: 10.1182/blood-2006-05-022087 -
Platelets Dec 2023Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal... (Review)
Review
Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal platelet function, which can subsequently lead to impaired hemostasis. In the past decades, humanized mouse models (HMMs), that are mice engrafted with human cells or genes, have been widely used in different research areas including immunology, oncology, and virology. With advances of the development of immunodeficient mice, the engraftment, and reconstitution of functional human platelets in HMM permit studies of occurrence and development of platelet disorders including IT and treatment strategies. This article mainly reviews the development of humanized mice models, the construction methods, research status, and problems of using humanized mice for the study of human thrombopoiesis.
Topics: Animals; Mice; Humans; Disease Models, Animal; Blood Platelets; Thrombopoiesis; Thrombocytopenia; Blood Platelet Disorders; Hematopoietic Stem Cell Transplantation
PubMed: 37849076
DOI: 10.1080/09537104.2023.2267676 -
Haematologica Dec 2016
Topics: Animals; Hippo Signaling Pathway; Humans; Metabolic Networks and Pathways; Protein Serine-Threonine Kinases; Signal Transduction; Thrombopoiesis; Tumor Suppressor Protein p53; rhoA GTP-Binding Protein
PubMed: 27903710
DOI: 10.3324/haematol.2016.156125 -
Blood Jan 2024
Topics: Bone Marrow; Megakaryocytes; Thrombopoiesis; Erythrocyte Membrane; Lung
PubMed: 38236613
DOI: 10.1182/blood.2023022897 -
British Journal of Haematology Apr 2014
Topics: Blood Platelets; Humans; Megakaryocytes; Thrombopoiesis
PubMed: 24690043
DOI: 10.1111/bjh.12799 -
Nature Communications Jul 2023Platelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms...
Platelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms remain unclear. Outside the body, however, our ability to generate large number of functional platelets is poor. Here we show that perfusion of megakaryocytes ex vivo through the mouse lung vasculature generates substantial platelet numbers, up to 3000 per megakaryocyte. Despite their large size, megakaryocytes are able repeatedly to passage through the lung vasculature, leading to enucleation and subsequent platelet generation intravascularly. Using ex vivo lung and an in vitro microfluidic chamber we determine how oxygenation, ventilation, healthy pulmonary endothelium and the microvascular structure support thrombopoiesis. We also show a critical role for the actin regulator Tropomyosin 4 in the final steps of platelet formation in lung vasculature. This work reveals the mechanisms of thrombopoiesis in lung vasculature and informs approaches to large-scale generation of platelets.
Topics: Mice; Animals; Blood Platelets; Microfluidics; Megakaryocytes; Thrombopoiesis; Lung
PubMed: 37419900
DOI: 10.1038/s41467-023-39598-9